Cells with multidrug resistance (MDR) due to aberrant expression of the lipid transporter P-glycoprotein (P-gp) display a wide range of biochemical changes that affect membrane lipid composition. Despite an established role for sphingomyelin (SM) as precursor to the pro-apoptotic second messenger ceramide in the action of numerous chemotherapeutic drugs, there has not been a major focus on the potential role of altered SM metabolism in P-gp action.
P-gp (ABCB1) is a member of the ATP-binding cassette (ABC) superfamily, which exports structurally diverse hydrophobic compounds from cells, driven by ATP hydrolysis (4). P-gp overexpression is considered to drive efflux of chemotherapeutic drugs in human cancers, leading to MDR. P-gp substrates partition into the lipid bilayer before interacting with P-gp, which has been proposed to act like a hydrophobic vacuum cleaner. Functionally, P-gp acts as an outwardly-directed phospholipid and sphingolipid flippase, suggesting it translocates drugs from the inner to the outer leaflet of the plasma membrane. Cancers considered chemoresistant such as renal cell, adrenocortical and colon cancer often display spontaneously high levels of P-gp, while other cancers such as leukemias develop high P-gp expression during therapy.
While P-gp MDR has often been associated with increased glucosylceramide synthase activity and increased glucosyl-ceramide, which mislocalizes to plasma membrane, a detailed analysis of the sphingomyelin/ceramide axis in cells displaying P-gp-mediated MDR has not been published. Furthermore, despite significant clinical effort, no effective therapy currently exists to reverse P-gp-mediated MDR in human cancers. Thus, the need exists for methods and compositions to overcome chemoresistance.